Note: On May 4, 2020, the Indian Council of Medical Research registered a hydroxychloroquine trial for its use as a prophylactic drug on the Clinical Trial Registry of India. This followed extensive reporting on the issue by Priyanka Pulla for The Wire Science, including the following article.

The Indian Council of Medical Research (ICMR) recently issued a clarification on a study to evaluate the prophylactic efficacy of hydroxychloroquine against COVID-19 – but the clarification has only raised more questions about whether ICMR is really groping in the dark with this unproven drug.

After Raman Gangakhedkar, ICMR’s chief of epidemiology, spoke repeatedly of a study to evaluate hydroxychloroquine, The Wire Science asked for more details. In a press conference held on Saturday, Gangakhedkar responded that he had been talking of an observational study with 480 patients, expected to go on for about eight weeks. He added that it was not a clinical trial because there wasn’t enough evidence to conduct such a trial.

These statements are illogical – and they also contradict what Gangakhedkar himself has previously said. In an April 1 press conference, he had said hydroxychloroquine was already being given to healthcare workers as part of a “demonstration study”. However, on Saturday, he spoke about the study in the future tense, suggesting that it hadn’t yet commenced.

So, has the study begun or not? If it hasn’t, why the delay, given that thousands of healthcare workers across India are already popping the drug?

The second question is why ICMR chose to conduct an observational study instead of a randomised controlled trial (RCT). India is likely the only country in the world where a government scientific agency has recommended the use of hydroxychloroquine as prophylaxis. And Gangakhedkar claimed on April 1 that the results of the demonstration study would be used to decide if the drug could be given to people in the community at large.

If this was the purpose of the demonstration study, an observational design is ill-suited to meet it. Researchers choose to perform an observational study when it is difficult to perform an RCT, for reasons ranging from the higher cost of RCTs to ethical issues in denying potentially effective drugs to the people in the study’s control group1.

Observational studies provide no information on causation: they can’t show whether hydroxychloroquine is responsible for preventing the disease (or not). “If you want to prove a point, you should do a well-designed randomised control study. Any other design will not give you convincing proof, and you are back to square one,” said Urmila Thatte, a clinical pharmacologist and bioethicist at the Seth GS Medical College and KEM Hospital, Mumbai, said. “Why do you want to waste your time and money doing a poor quality study?”

Gangakhedkar’s statement that there was not enough evidence in favour of hydroxychloroquine to conduct a randomised trial is more bizarre. A lack of evidence is the perfect scenario in which to conduct an RCT – as well as the worst scenario in which to recommend the drug to healthy individuals, like ICMR has done. The agency’s decision to jump the gun on evidence has since encouraged the Brihanmumbai Municipal Corporation to consider giving the drug to 50,000 people in the city’s Dharavi and Koliwada areas. A COVID-19 outbreak is currently on in these places, whose population belongs mostly to the middle and lower economic classes.

A second study… and then a third

Adding to the existing confusion, Gangakhedkar referred in the Saturday press conference to two new studies on hydroxychloroquine as prophylaxis, both of which neither he nor anyone else has mentioned before.

The second study, according to him, involved healthcare workers who had begun taking hydroxychloroquine on their own, when ICMR had announced its first observational study. These workers, he said, were being monitored for adverse effects. He revealed some details of this group: their average age was 35 years and the most common adverse side-effect, in around 10% of participants, was abdominal pain, followed by nausea (6%) and hypoglycaemia (low blood sugar: 1.3%). Gangakhedkar did not reveal if the study had a control group, and what the various adverse effects were in that group.

Gangakhedkar also revealed a worrying detail: that among all the healthcare workers participating in this study, 22% had diabetes, blood pressure, cardiovascular disease or respiratory illnesses. And yet, some 14% of them had not got an electrocardiogram (ECG) before starting to consume the drug. This is a problem because some of these ailments, and the drugs used to treat them, could predispose these people to the deadlier effects of hydroxychloroquine, such as arrhythmia, moreso since ICMR had also recommended a high initial dose. An ECG is recommended to help rule out the risk of arrhythmia. And Gangakhedkar admitted that even healthcare workers, who ought to know better, hadn’t undergone the tests.

The litany of questions goes on. For another, why does ICMR’s study on adverse effects of the drug not appear on the Clinical Trial Registry of India (CTRI)? Searching for the terms “hydroxychloroquine” and “covid” didn’t return this study in the search results, nor in fact the other two. According to Thatte, India hasn’t yet mandated that researchers register their observational studies beforehand, but it is good practice to do so.

This is because publishing a study’s design in advance discourages researchers from manipulating the design to report more favourable outcomes after the study has concluded. This happens often: scientists set out to test whether X is true, find out Y is true, and tweak their report to only discuss Y.

For example, criticism of one of the first few clinical trials investigating the effects of hydroxychloroquine against COVID-19, by a French group led by microbiologist Didier Raoult, became possible because Raoult’s group had registered their trial in advance. This allowed another group of researchers from Ireland and the UK to note that Raoult’s group had inappropriately dropped six trial participants from their final analysis, potentially making hydroxychloroquine look better than it really was.

Given that CTRI is run by the National Institute of Medical Statistics, which is governed by ICMR, one would expect ICMR to have registered its study (or studies).

Not enough participants?

Gangakhedkar also referred to a third trial, being conducted by the All India Institute of Medical Sciences; it isn’t clear which of India’s 15 AIIMS he was referring to. This trial is apparently testing chloroquine for its prophylactic and treatment efficacy against COVID-19. Here again, Gangakhedkar didn’t specify whether it was an observational study or an RCT. Because many healthcare workers are already consuming the drug, he suggested ICMR was having a tough time finding “homogenous” groups of people who were on the drug and off it.

The nephrologist Vivekanand Jha, of the George Institute for Global Health, New Delhi, had recently co-authored an article in The Hindu saying ICMR’s hydroxychloroquine advisory would make clinical trials harder because researchers will be hard-pressed to find healthcare workers willing to skip taking the drug (for the control group). And Gangakhedkar’s revelation seems to confirm that this problem is now plaguing the agency’s own research.

It increasingly looks like ICMR’s advisory on hydroxychloroquine is backfiring. According to a recent letter that four Indian doctors sent to The Lancet, “A blanket recommendation for chemoprophylaxis in the absence of credible evidence might be contentious to say the least.” After its own contentious recommendation, the least ICMR could have done was to collect credible evidence of the drug’s efficacy. But it doesn’t seem to be doing this – which is a huge injustice to the many Indians who have been taking the agency’s word as gospel.